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| | ==Structure of Mycobacterium tuberculosis DXR in complex with a fosmidomycin analogue== | | ==Structure of Mycobacterium tuberculosis DXR in complex with a fosmidomycin analogue== |
| - | <StructureSection load='3zhx' size='340' side='right' caption='[[3zhx]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='3zhx' size='340' side='right'caption='[[3zhx]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3zhx]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZHX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZHX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3zhx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZHX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZHX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FM6:[(1S)-1-(3,4-DICHLOROPHENYL)-3-[OXIDANYL(PHENYLCARBONYL)AMINO]PROPYL]PHOSPHONIC+ACID'>FM6</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3zhy|3zhy]], [[3zhz|3zhz]], [[3zi0|3zi0]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FM6:[(1S)-1-(3,4-DICHLOROPHENYL)-3-[OXIDANYL(PHENYLCARBONYL)AMINO]PROPYL]PHOSPHONIC+ACID'>FM6</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/1-deoxy-D-xylulose-5-phosphate_reductoisomerase 1-deoxy-D-xylulose-5-phosphate reductoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.267 1.1.1.267] </span></td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3zhx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zhx OCA], [https://pdbe.org/3zhx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zhx RCSB], [https://www.ebi.ac.uk/pdbsum/3zhx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zhx ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3zhx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zhx OCA], [http://pdbe.org/3zhx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3zhx RCSB], [http://www.ebi.ac.uk/pdbsum/3zhx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3zhx ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DXR_MYCTU DXR_MYCTU]] Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP) (By similarity). | + | [https://www.uniprot.org/uniprot/DXR_MYCTU DXR_MYCTU] Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP) (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[DXP reductoisomerase|DXP reductoisomerase]] | + | *[[DXP reductoisomerase 3D Structures|DXP reductoisomerase 3D Structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 1-deoxy-D-xylulose-5-phosphate reductoisomerase]] | + | [[Category: Large Structures]] |
| - | [[Category: Myctu]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Bergfors, T]] | + | [[Category: Bergfors T]] |
| - | [[Category: Bjorkelid, C]] | + | [[Category: Bjorkelid C]] |
| - | [[Category: Jansson, A M]] | + | [[Category: Jansson AM]] |
| - | [[Category: Jones, T A]] | + | [[Category: Jones TA]] |
| - | [[Category: Mowbray, S L]] | + | [[Category: Mowbray SL]] |
| - | [[Category: Unge, T]] | + | [[Category: Unge T]] |
| - | [[Category: Doxp/mep pathway]]
| + | |
| - | [[Category: ISPC, Israel Structural Proteomics Center]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Rv2870c]]
| + | |
| Structural highlights
Function
DXR_MYCTU Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP) (By similarity).
Publication Abstract from PubMed
The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway, producing the essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Calpha and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM.
DXR inhibition by potent mono- and disubstituted fosmidomycin analogues.,Jansson AM, Wieckowska A, Bjorkelid C, Yahiaoui S, Sooriyaarachchi S, Lindh M, Bergfors T, Dharavath S, Desroses M, Suresh S, Andaloussi M, Nikhil R, Sreevalli S, Srinivasa BR, Larhed M, Jones TA, Karlen A, Mowbray SL J Med Chem. 2013 Aug 8;56(15):6190-9. doi: 10.1021/jm4006498. Epub 2013 Jul 17. PMID:23819803[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jansson AM, Wieckowska A, Bjorkelid C, Yahiaoui S, Sooriyaarachchi S, Lindh M, Bergfors T, Dharavath S, Desroses M, Suresh S, Andaloussi M, Nikhil R, Sreevalli S, Srinivasa BR, Larhed M, Jones TA, Karlen A, Mowbray SL. DXR inhibition by potent mono- and disubstituted fosmidomycin analogues. J Med Chem. 2013 Aug 8;56(15):6190-9. doi: 10.1021/jm4006498. Epub 2013 Jul 17. PMID:23819803 doi:http://dx.doi.org/10.1021/jm4006498
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